The two-day exercise study results suggest that the ability to produce energy after exercise in chronic fatigue syndrome (ME/CFS) is blunted, and the search is on to identify blockages in cellular energy that could explain that. Lead by Cara Tomas, Julia Newton and company have stepped into the fray with the first published “Seahorse” ME/CFS study that I’m aware of.

Agilent’s Seahorse machine is, for the first time, making it easy for researchers to study cellular energetics. During a recent trip to Nancy Klimas’s lab at Nova Southeastern (she has one) Dr. Deth exclaimed at how the Seahorse has greatly expanded researchers ability to put cells under stress and measure their energy production. With at least five ME/CFS studies using the machine, the Seahorse is a case of technology evolving at just the right time to benefit ME/CFS research.

Because there’s no evidence that genetic mutations are affecting mitochondria output in chronic fatigue syndrome (ME/CFS), any mitochondrial problems that are present they are most likely “acquired” during an infection or other event which either damaged them or prevented them from functioning properly. Since the mitochondria can be inhibited by a number of factors ranging from immune activation to oxidative stress to psychological stress it’s probable that a number of different pathways lead to any mitochondrial dysfunction that might be present in ME/CFS.

An earlier study using a different means of measuring cellular energy production (ATP Profile test) in neutrophils in whole blood found that “all patients tested have measureable mitochondrial dysfunction which correlates with the severity of the illness.” Cell-free DNA measurement showed high levels of damage.

Other studies, however, do not suggest the mitochondrial play an important role in ME/CFS. Mitochondrial content was lower in ME/CFS but ATP production and other measures of mitochondrial health were normal. Likewise, Vermeulen found reduced exercise capacity in ME/CFS but normal ATP production. If an inhibiting factor in the blood plays a role Vermeulen’s extraction of PBMC’s from whole blood might have played a factor. Vermeulen, however, proposed that reduced oxygen delivery to the issues was the problem.

Most recently, a Stanford study found evidence of greatly increased mitochondrial activity in ME/CFS cells. The Stanford study suggested that left to themselves the mitochondria in ME/CFS might doing just fine and that glycolysis – the anaerobic portion of the energy cycle – might be the issue.

“Our results present an unorthodox view on CFS pathology: the fatigue is not caused by lack of ATP, and instead might be caused by a pathological process linked to non-mitochondrial ATP production such as glycolysis.”

That study, which did not use the Seahorse machine, provided yet another twist when the glycolysis results suggested that ME/CFS was a hyper not a hypometabolic conditions. Because the cells were tested outside of the plasma the effect of a possible inhibiting factor in the blood was not taken into account.

Now we have Tomas et. al. using the Seahorse machine to get very accurate direct measurements of cellular energy production in ME/CFS. Like Vermulen, this group used PBMC’s isolated from whole blood.

Stuck Cells

The first sign something was wrong came when Tomas assessed the energy production of cells low and high glucose concentations. (The Seahorse machine allows researchers to add materials to the cells to see the effect they have on energy production.) Tomas expected the addition of glucose would boost up glycolysis – the anaerobic portion of the energy cycle which runs on glucose – and it did – but only in the healthy controls. The inability of the ME/CFS patient’s cells to utilize the extra glucose seemed to suggest that something had gone wrong with glycolysis in ME/CFS but a glycolysis stress test indicated that glycolysis was operating normally.

Almost every indicator of energy production was lower in ME/CFS patients cells whether they were put into low or high glucose levels (basal respiration, ATP production, maximal respiration, reserve capacity, non-mitochondrial respiration, coupling efficiency).

Newton suggested that the ME/CFS cells were kind of stuck in a low energy mode. When given extra glucose they weren’t able to use it. When deprived of glucose they weren’t able to increase their mitochondrial energy production. A stimulation test in the Seahorse machine didn’t stimulate the ME/CFS patient’s cells much either. When asked to respond the ME/CFS cells were able to generate about 50% more energy while healthy control cells doubled their energy output. The study was on immune cells not muscle cells but each finding seemed to make sense given ME/CFS patient’s inability to mount the energy to engage in exercise.

The healthy controls cells, on the other hand, responded to all three tests – they basically demonstrated the flexibility and capacity that healthy cells need to have to respond adequately to a number of different situations.

Newton’s explanation about the healthy control cells being more “adaptable” or responsive to their environment than the ME/CFS patient’s cells sounded somewhat like Bob Naviaux’s idea of the cells being thrown into a cell danger response and hunkering down and trying to ride out some threat. Unless Naviaux’s CDR hypothesis includes cells getting stuck without an outside factor to keep them reined in (which it may), however, it didn’t seem to apply: Newton’s cells were tested outside of the plasma where the threat is believed present.

Beside their unresponsiveness the ME/CFS patient’s cells also had lower reserve capacity; i.e. they may have already been operating near their maximum level. The low coupling efficiency suggested that when pushed, they simply didn’t have the resources to respond.

All in all it was a remarkable set of findings. At least two thirds of the tests done were abnormally low in whatever situation they were put in.

A earlier model of mitochondrial dysfunction in ME/CFS seems, at least to this laymen’s eyes, reflect the situation Newton found. When stressed the cells lacked the capacity to respond. Their reduced mitochondrial capacity had caused the cells to dig into their adenine reserves resulting in long recovery periods after exercise. The model predicted it would take 3-5 times longer for the ATP levels in the muscles of ME/CFS patients to return to normal after exercise than for healthy controls. The model also predicted that short (30 seconds), intense exercise periods would be easier for ME/CFS patients to recover from.

Newton’s findings certainly seemed to make sense given the fatigue and energy problems highlighted in ME/CFS but, as she acknowledged, they conflicted with some of the past results.

The combination of the detection of significant differences in OXPHOS alongside the lack of detectable differences in glycolysis has potentially uncovered a previously unknown phenotype of CFS PBMCs Newton et. al.

Newton isolated ME/CFS patients PBMC’s from whole blood but still found reduced cellular energy production. The Stanford group did the same thing but found increased energy production with a highlight on increased glycolysis. Newton’s finding of reduced energy production in cells found outside the plasma suggests that problems may exist in the cells themselves.

Newton’s findings of normal glycolysis conflicted with the Stanford group’s finding on increased glycolysis and with metabolomic studies pointing to glycolysis issues.

In broad way, though, Newton’s findings do fit. Almost all the studies point to problems with cellular energy production that may be manifesting themselves in different ways. A somewhat similar situation may be showing up in exercise studies where different issues (ventilation, VO2 max, anaerobic threshold) are appearing in different patients. Those studies suggest that the exercise incapacity present in ME/CFS is being produced different ways. That may not be surprising given what we know about disease. If the molecular roots of say, lung cancer, differ between patients, it would make sense for a variety of different pathways to cause the energy production problems in ME/CFS.

Conclusion

Newton’s rather stunning findings – that the vast majority of tests of cellular energy production were significantly lower in ME/CFS patients’ immune cells – made sense. The good news is that most studies are finding evidence of whole body (exercise, metabolomics) or cellular energy production problems. The bad news is that they’re coming to different conclusions as to how that’s happening.

The cure to the energy production puzzle is, of course, bigger and better studies and they seem to be coming. The Seahorse machine, which looks like it’s going to be floating around ME/CFS research circles for a while, will mean more methodological consistency and allow for better comparisons between studies.

Avindra Nath is using one in his NIH intramural study, and Maureen Hanson appears to be using one in two studies, one of which will hopefully be a large, robust study at her NIH funded ME/CFS research center. Ron Davis has used one, Isabel Barao is using one in her SMCI funded study, and Newton reported she will be seeking larger, longitudinal studies. Anyone, it seems, who wants to know about energy production in ME/CFS is using one.

Avindra Nath’s intramural study is small – approximately 40 patients – but with its metabolic chamber, exercise study and other features it’s digging into so many different parameters that one wonders if it might be able to uncover different subsets and their pathways all on its own. Brian Vastag reported that the early Seahorse results were so unusual that the researcher involved felt compelled to stop by and chat…

By the time all is said and done the Seahorse will hopefully tell us much about ME/CFS.

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45 Comments

Cecelia
on November 11, 2017 at 8:40 am

There is a typo which is confusing re the Stanford study conclusion about ME/CFS being perhaps a hypermetabolic condition instead of a hypermetabolic condition—It is under the “box” above, which seeks contributions.

Anyway, once I got to your conclusion and news that multiple researchers are using the Seahorse now and are communicating with each other on their studies—that is gratifying news!

“Newton’s finding of reduced energy production in cells found outside the plasma appears to conflict with the idea that something in the blood is whacking ME/CFS patient’s cells ability to produce energy”

Perhaps it’s the other way round, then – that healthy people have something in the plasma that will help cells produce, even if under-producing, whereas ME/CFS patients don’t.

Is it really that hard to know what’s in plasma, what the difference is between two samples?

Absolutely. I believe Ron Davis is both filtering factors out of plasma to see if they are the problem and adding factors to cells to see they effect them. If I remember correctly, Davis has found that the factor is likely large in size (like an antibody) and that Suriman, ATP and pyruvate help ME/CFS cells energy levels. As I remember I think its likely that the nano-needle is measuring energy levels but more work needs to be done to pin that down.

Yes it does. I believe both Ron Davis/ Open Medicine Foundation and Fluge and Mella are trying to find out what’s present in the plasma.

Katherine Autry
on November 11, 2017 at 10:51 am

This reminds me of how they establish hypothryoid conditions, by testing for Thyroid Stimulating Hormone. If it is too HIGH, it means that not enough thryoid hormone is being produced. (Seems counterintuitive, like this situation with ATP). But what if the high levels of ATP production – without a corresponding increase in usable energy – have a similar mechanism? Could it mean that the body is sending “MAKE MORE” signals not because there isn’t enough ATP in the body, but because the ATP isn’t reaching it’s destination (ie, brain, muscle)?

Maybe the break isn’t in the manufacturing process but rather in the packaging or delivery system. Or maybe the break is in the cells on the receiving end, ie cell walls in brain and muscle are damaged and can’t receive the ATP at the required levels or speed to function properly (ie, no one is home to sign for the package). Thus these cells are starving, in the midst of plenty, and keep signalling for more to be produced.
And Maybe the excess ATP in the body is causing its own problems on top of everything else.

The Stanford study found increased energy production so it suggested that hypermetabolism was present but the cells were tested outside the plasma. Now, this study suggests that hypometabolism is indeed present but it used a different technique – the Seahorse machine – and the sample size, as the authors noted, was pretty small.

It remains an extraordinary thing that after thirty years of applying sophisticated technology, CFS researchers still remain unable to discover what they could have known by simply reading the newspapers about the original CFS incident.

Even more so, their unusual behavior of disinterest whenever they are shown evidence of what they overlooked.

And what, may I ask, is “the original CFS incident”? Are you talking about Lk Tahoe? If so, you are incorrect. Some of us were sick more than four or five years before this incident.
Thank you, Cort. We’re getting closer!!

If ME were a hypermetabolic condition, could the contradiction in cellular research results point to a depletion in key enzymes (both for anaerobic and aerobic energy production)? If our cells work hard for very few results almost all of the time then it could easily deplete key enzymes especially in a toxic and dysfunctional environment. It would greatly reduce their ability to adapt to changing demand. The longer time for cells to recover could fit the longer time to replentish these enzymes?

Wasn’t there ME research that pointed to lacking a key enzyme in the cellular energy production? If production of these enzymes was not the problem but consumption, measurements on the presence of enzymes could easily contradict each other depending on cell load and resting between loads.

I don’t know where these enzymes are produced and where they’ll come from when depleted, but if they were both in the cells and in the blood it could make sense. ME cells in healthy blood could be replenished by sufficient enzymes and work relatively fine. A few healthy cells in a see of ME blood could see their enzymes difuse from the high concentrations in the cells to the low concentrations in the blood. After a while their enzyme content would be close to ME cells in ME blood so it could make them fail too. Who knows? So much questions. LondonPots ideas inspired me.

I think a large part of enzymes are used in the gut. However I’m no expert. But I’ve been tempted to try the same enzymes doctors prescribe to people who’ve successfully survived massive organ surgery for pancreatic cancer. I have seen this discussed elsewhere.

enzymes are used/needed in many conversions from one molecule to another. They are also essential in anaerobe and aerobe energy production.

See for example https://en.wikipedia.org/wiki/Fructolysis on top of the article:
“Though the metabolism of glucose through glycolysis uses many of the same enzymes and intermediate structures as those in fructolysis, …”

See also: https://en.wikipedia.org/wiki/Citric_acid_cycle
See the big/first table: *every* single conversion in the citric acid cycle better known as Krebbs cycle (key to mitrochondria functioning) needs an enzyme listed in the table. Sometimes even the concentration of enzymes is regulated by other enzymes.

Cort,a very informative article for an old Fatigue researcher to read. In fact, I’m recovering from a relapse into CFS and catching up. Mind scratching research on energetics. Also a bit of nit-picking, NO muscles are truly anoxic even at max exercise. It would be better to describe glycolysis as non-aerobic rather than anaerobic. Also we CFSers have reduced capacity rather than incapacity and are hypo-responsive than unresponsive. Reminds me of hallway conversations with Bryan Whipp.
Ninteenth paragraph down starts with “A earlier model….” Will you send me a link for it. Again, super work your are doing. Thanks.

The statement in the article
“…If an inhibiting factor in the blood plays a role Vermeulen’s extraction of PBMC’s from whole blood might have played a factor. Vermeulen, however, proposed that reduced oxygen delivery to the issues was the problem.”

made me think about what I’m currently doing.

Firstly I have what is considered normal oxygen saturation levels (around 98%) although that’s never been tested ‘during’ exercise. I suspect it could be reduced a little more.

Anyway I’ve felt like I’m starving for oxygen a lot of the time. So I got a loan pulse oxygen machine.
I have been testing the machine on myself and have by either coincidence or placebo or actually biologically felt a lot better. Early days yet as only 2 weeks of use, so I could be in some sort of normal remission by chance. But I have been using it during and after all types of exertion. Especially when my heart rate goes above my aerobic threshold (AT).
Normally if I go over my AT I end up after 24 to 48hrs of feeling normal, suddenly struck down with PEM (flu like symptoms) that can last 2 days to 10 days. But I haven’t had PEM since using the oxygen machine. I’m still fatigued (less so) but importantantly to me I’m not feeling those really sickly, unwell flu like sensations. I still have brain fog but it is slightly reduced too.

One has to be careful not to develop oxygen toxicity so read up on that. Maybe only during exertion and 10 mins to 30 mins after. Talk to your doctor

Has anyone else tried oxygen?
It’s not a cure but maybe a symptom reducer

Do you know if the studies you referred to are appropriately factoring in O2 consumption measurements into their interpretation of the acidification measurements for inferring glycolysis (see Mookerjee et al. Biochim Biophys Acta. 2015 Feb;1847(2):171-81. ”
The contributions of respiration and glycolysis to extracellular acid production.” Otherwise, their inferred glycolysis rates are confounded by aerobic metabolism.

Nevermind my previous comment. It appears that the scientists doing the work referred to in my previous comment were consultants with Seahorse Biosciences, which developed the “Seahorse machine” (and was sold to Agilent). So, I believe that the above studies did appropriately account for potential confoiunding of glycolysis measurements by aerobic activity. Sorry for the distraction.

I thought he had disappeared from cfs research but obviously not! The press release does not give much detail so it will be good to get a better understanding of what his findings are.

Merida
on November 12, 2017 at 1:34 am

Many years ago I kept getting blood work demonstrating low levels ( 60 to 70% of normal) of the enzyme lactate dehydrogenase. ( My doc was testing this to make sure the LDH wasn’t elevated – found in certain disease processes.) LDH catalyzes the interconversion of lactate and pyruvate, and NAD + to NADH. Thus, this enzyme is a critical part of anaerobic glycolysis.

There are 5 isoforms of LDH that are enzymatically similar, but show different tissue distributions. LDH -1 is concentrated in the heart, red blood cells, and brain.

So, I read as much as I could find on this topic, and found that LDH deficiency was considered ( by some researchers, at that time??? ) a glycogen storage disorder. There was no research on minor deficiencies of this enzyme, but considering that mature red blood cells have no mitochondria, and depend on anaerobic mechanisms, I thought this could be important.

Past observation and thinking had led me to the conclusion that CFS/FMS families, including mine) have multiple minor ( or not so minor) congenital structural differences. I led a large support group 13 years, and spoke with many families. These issues came up over and over again: spina bifida occulta ( missing section of L-5), congenital heart issues, various kidney anomalies, redundant colons ( a variant of malrotation/ malattachment of the gut), pelvic floor anomalies, hypodevelopment of the sacrum( i.e.small foramina) and so much more. It is, as if, there was not quite enough energy to fully complete the ‘job.’ It is interesting that early fetal development depends on anaerobic metabolic pathways, but this gets complex, and I can’t remember any more than that.

Further thinking and reading made me wonder if the important part of the disrupted, genetically controlled, energy deficiencies due to a particular enzyme deficiency, might be the resulting structural differences that then become important: small posterior fossae, short filum terminale, scoliosis, boney pelvic/sacrum anomalies, structural heart/ kidney issues, and so on.

Check out Maureen Hanson’s presentation at the Community Symposium on the Molecular Basis of ME/CFS. She presented data showing altered mitochondrial energy production (consistent with these results); however, Hanson didn’t find evidence that glycolysis was impaired.

There are some suggestions that this study is finding activation/clonal expansion of T cells; check out Mark Davis’s presentation at the symposium.Is it possible to repeat this study using activated/non-activated T cells?

Good to hear that “both Ron Davis/ Open Medicine Foundation and Fluge and Mella are trying to find out what’s present in the plasma” i.e. affecting cell metabolism in ME/CFS.

The issue, in my CFS, was in fact cellular energy downregulation. This same type of hunkering down you’re referring to. But. There’s a reason this is happening, and it isn’t a virus, pathogen, or some otherwise outside threat, but rather: a metabolic shift toward using fatty acids and amino acids for a fuel substrate, and a down-regulation of the more efficient glucose energy production system.

But why? The answer: high fat consumption, mixed with low to no carbohydrate consumption, mixed with intense exercise (usually).

It’s actually prolonged ketogenic or Atkins like diets that contribute to inducing CFS in people.

Fat adaptation IS REAL, and is a total Fucking disaster metabolically for peope, which is the opposite of the low carb community’s contention that it’s a good thing.

I had CFS. Had. And before anyone says… “you couldn’t have had CFS if you don’t have it anymore..”…. let me just ask: are you willing to remove dogma and harmful beliefs to get better?

Is it possible to, through a large and consistent re-sensitizing of cells to use glucose to produce energy through a tuber and starch centric diet for a while, reverse the hunkered down, energy conserving, fatty acid using, glucose metabolism impaired fatigue state typically called CFS?

Is it possible? Yes. I did it. I was bed ridden for nearly 2 years with CFS. Blood tests = good. Fasting glucose a bit high, but nothing major.

But impaired. Insanely sick. Everyone thought I was making it up. Doctors had nothing for me.

But today I sit, doing sprints when I wake up, lifting heavy weights in the evening, in the best shape of my life, running two businesses. Largely cured. Fatigue I may experience these days is in the normal range, and I experience GREATER ENERGY than my peers who have never had the disease.

How did I do it?

I trained my body to use glucose adequately again. I forced it too, actually, by consuming large quantities of starch, forcing myself to run through the exhaustion (which cleared in about two weeks), and sensitized insulin again via avoiding both fat AND refined sugar, while gradually lifting weights.

I forced it. Forced. Just like I forced it to use ketones and amino acids 4 years ago when I went ketogenic for 9 months, and exercised like a triathelete.. which caused the casquade of cellular energy metabolism changes that caused my CFS.

This research… on metabolic switching is NEW as it relates to CFS, and YOU CORT, are on the right track highlighting it.

THIS IS IT. This is it. This is the silver bullet everyone’s been waiting for, and everyone is going to have to figure out how THEY are going to jumpstart the glucose utilization pathways again.

Ryan, how great that your approach worked so well for you, but keep in mind the vast majority of us with CFS don’t (and never have) followed a true ketogenic for any length of time. Like many, I have tried just about every reasonable kind of diet, taking a ‘nothing to lose’ approach. Regrettably nothing has made the slightest difference. Btw, I came down with CFS in 1983 while eating macrobioticly – about as low-fat as you can go.

I feel like I’m in over my head in trying to understand a lot of this. I just don’t have the background.

However, this may be related:
My chiropractor had me do a blood test with Brain Span (www.brainspan.com). The theory is that if your Omega 6 and Omega 3 balance is not at or close to 1.1 then your cellular walls are not sufficiently permeable. I am taking 2,000mgs of combined DHA and EPA to correct the imbalance. It has only been a few days, and I do feel the inflammation and pain is less.

Ryan,
It is interesting that the Glycogen storage Disease, type 1, is treated with corn starch, and low fructose/ glucose. These people have inadequate or nil glucose 6 – phosphatase. Have you been tested??

The glycogen storage disorders may be important. There many enzymes involved in the metabolic pathways, and perhaps we have a new, yet to be described GSD. Viruses can also mess with mitochondrial energy production.

I’m so glad they are doing this research to find out the physical causes of low energy. I have fibro, which also has a low energy coponent, although nothing like CFS.

I hope they look for infectuous agents. It may be a completely new type of infectuous agent or one that is “hiding” under a biofilm . Would they be able to find it, if that is the case?

The reason why I ask is that I keep reading about what they are finding with exposure to mold and also what they are finding with Lyme and how an infectious agents are able to protect themselves through a biofilm from being identified and treated. Our tests don’t detect it. It is an intriguing thought that perhaps there is an infectuous agent with fibro/CFS that is doing the same thing.

Having lived with fibro for over 30 years, my best “guess” is that it some kind of unknown disease carrying agent that certain individuals are genetically susceptible to and that we haven’t found yet. There are many reasons for my thinking that I won’t go into now becuase of space, but if I remember correctly, CFS first started manifeseting in clusters in different parts of the country. One was in Incline Village, NV, in the late 70s/early80s. We visited there during that time, and it’s around that time I first sought medical treatment for the condition that was later diagnosed as fibro, (not CFS). I have no proof of a causal relationship, and I’ve read they may be separate conditions or they may be one with fibro on one end of the spectrum manifesting with pain, and cfs on the other with debilitating fatigue.

Several 1st and 2nd degree female relatives on one side of my family were diagnosed with the condition during early adulthood, and that seems to be not uncommon, so it does seem as though there is a genetic predisposition in some people.

What do you think, Court, about the HPV6 hypothesis? That fibro is latent herpes 1 infection that is triggered later in life in genetically susceptible individuals?

Thanks for all you do for the community! Your contribution is truly incalculable, with all of the disinformation out there. You can’t take a general practitioner at face value; they simply aren’t educated about the conditions. Some specialists aren’t either.